Regulatory T cells (Treg) are the main causative cells inducing immune tolerance that is observed in the tumor area of cancer patients. That is to say, in cancer patients, groups of immune cells that intrinsically work to kill tumors are rendered into a state of immune suppression by activated Treg in the tumor, and this leads to the malignant progression of the tumor [Non Patent Literature 1].
Glycoprotein-A Repetitions Predominant (GARP) is a protein with a single-pass transmembrane structure [Non Patent Literature 2], and this protein is expressed on the cell surface of activated Treg and forms a complex with latent TGF-β (a precursor of TGF-β which is an important molecule for inducing immune tolerance) [Non Patent Literature 3].
As a result of the cell-cell interaction between Treg and target cells to which the Treg induces immunosuppression, TGF-β is matured from latent TGF-β by GARP on the cell surface of Treg and secreted from Treg, and the immunosuppressive signals of TGF-β are directly transmitted to the target cells [Non Patent Literature 4, 5]. It has been demonstrated that the membrane-bound GARP expressed on the cell surface is necessary for such maturation of TGF-β [Non Patent Literature 5]. On the other hand, it has also been demonstrated that soluble GARP that lacks a transmembrane region suppresses proliferation of CD4 positive T cells when it is directly added to the cell culture [Non Patent Literature 6]. Thus, it cannot be ruled out that there is an immunosuppressive mechanism of GARP which does not require TGF-β maturation on the cell membrane.
GARP is not only expressed by Treg from peripheral blood when they get activated, but also in a clinical setting by tumor infiltrating T cells at tumor sites of cancer patients [Non Patent Literature 7], by Treg existing in ascites [Non Patent Literature 8], and also by Treg circulating in the peripheral blood of cancer patients [Non Patent Literature 9].
In a report investigating the effect of inhibition of GARP expression on the function of Treg, siRNA-targeting GARP inhibited the immunosuppressive function of Treg on the proliferative responses of helper T cells, but such an inhibitory effect was partial [Non Patent Literature 10].
In another report, anti-GARP antibodies (MHG-8 and LHG-10) which had been obtained for their abilities to inhibit TGF-β maturation inhibited the suppressive function of A1 cells, which is a Treg cell line [Non Patent Literature 11] established from hemochromatosis patients, on the proliferative responses of helper T cells [Patent Literature 1 and Non Patent Literature 12]. However, it is not known whether or not the aforementioned antibodies effectively exhibit such inhibitory effects on Treg in a tumor microenvironment, and to date, no anti-GARP antibody having such effects has been reported so far. An antibody recognizing both GARP and TGF-β is also known [Patent Literature 2].
It has been demonstrated that the excessive presence and the activation of Treg in patients having malaria and HIV infection exhibit a correlation with the disease state [Non Patent Literatures 13 and 14], and that the removal of Treg resulted in remission of the disease state in murine models for the diseases [Non Patent Literatures 15 and 16].